Process for the preparation of (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane, novel processes for preparing an intermediate thereof, and novel intermediates thereof

ABSTRACT

The present invention relates to a novel process for preparing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane, also known in the art as (E)-(p-fluorophenethyl)-3-fluoroallylamine, novel intermediates thereof, a novel process for the preparing (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol, and a novel process for preparing alkali metal salts of diformylamide.

The present invention relates to a novel process for preparing(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane, also known inthe art as (E)-(p-fluorophenethyl)-3-fluoroallylamine, andpharmaceutically acceptable salts thereof, which are useful asirreversible inhibitors of monoamine oxidase U.S. Pat. No. 4,454,158,Jun. 12, 1984, to novel processes for the preparation of an intermediatethereof, and to novel intermediates useful in the preparation of(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane.

BACKGROUND OF THE INVENTION

A general process for preparing allyl amines including(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane is described inU.S. Pat. No. 4,454,158, issued Jun. 12, 1984. A process for preparing(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane is described inInternational Application No. WO 93/24120, (PCT) published Dec. 9, 1993and European Pat. Application No. 0 295 604, published Dec. 21, 1988.

These methods, however, have the disadvantage that some of the steps toprepare a useful intermediate, (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol, use reagents and conditions that do notallow for economical, large scale, production of(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol. Further, thesemethods use a phthalimide containing intermediate, the removal of whichgives (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butanecontaminated with phthalhydrazide which is difficult to remove from thefinal product.

The process of the present invention for preparing(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane utilizes alkalimetal salts of diformylamide. Generally, these salts are only partiallysoluble in useful solvents which causes the reaction rate to be surfacearea dependent.

The preparation and use of alkali metal salts of diformylamide is knownin the art. J. N. Rakshit, J. Chem. Soc., 103, 1557-1562 (1913); E.Allenstein and V. Beyl, Chem. Ber. 100, 3551-3563 (1967); H. Yinglin andH. Hongwen, Synthesis 7, 122-124 (1990); and H. Yinglin and H. Hongwen,Synthesis 7, 615-618 (1990).

The methods for preparing alkali metal salts of diformylamide, however,have the disadvantage that the material is obtained as a solid mass. Thesolid obtained must be broken up which leads to material of differingand irregular particle size. Moreover, milling alkali metal salts ofdiformylamide to increase the surface area creates dust and inhalationproblems. Further, the method of E. Allenstein and V. Beyl for preparingalkali metal salts of diformylamide, when carried out on large scale,gives material that is contaminated with detrimental amounts of methanoland ammonia.

An object of the present invention, therefore, is to provide novelmethods for the economical preparation of(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol which can becarried out without purification between steps.

Another object of the present invention is to provide a novel method forproducing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butaneutilizing intermediates which provide the final product withoutdifficult to remove by-products.

Another object of the present invention is to provide a novel processfor crystallizing alkali metal salts of diformylamide that gives alkalimetal salts of diformylamide as a free flowing granular solid that isfree of detrimental amounts of methanol and ammonia.

A further object of the present invention is to provide novelintermediates useful for preparing(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol comprising thesteps of:

a) reacting 4-(p-fluorophenyl)butyric acid with isobutylene to givet-butyl 4-(p-fluorophenyl)butyrate;

b) reacting t-butyl 4-(p-fluorophenyl)butyrate with an appropriate alkylchloroformate to give an alkyl2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate;

c) reacting an alkyl 2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyratewith an appropriate difluoromethane transfer reagent to give an alkyl2-(difluoromethyl)-2-t-butoxycarbonyl-4-(p-fluorophenyl)butyrate:

d) reacting an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate withan appropriate acid to give an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate;

e) reacting an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate with anappropriate base to give an alkyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate;

f) reacting an alkyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyratewith an appropriate reducing agent.

Furhter, the present invention provides a novel process for preparing(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol comprising thesteps of:

a) reacting 4-(p-fluorophenyl)butyric acid with isobutylene to givet-butyl 4-(p-fluorophenyl)butyrate;

b) reacting t-butyl 4-(p-fluorophenyl)butyrate with an appropriate alkylchloroformate to give a reaction mixture and then reacting the reactionmixture with an appropriate difluoromethane transfer reagent to give analkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate;

c) reacting an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate withan appropriate acid to give an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate;

d) reacting an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate with anappropriate base to give an alkyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate;

e) reacting an alkyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyratewith an appropriate reducing agent.

In addition, the present invention provides a novel process forpreparing (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane andpharmaceutically acceptable salts thereof comprising the steps of:

a) reacting (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol with anappropriate halogenating agent to give a(E)-1-halo-2-(fluoromethylene)-4-(p-fluorophenyl)butane;

b) reacting a (E)-1-halo-2-(fluoromethylene)-4-(p-fluorophenyl)butanewith an alkali metal salt of diformylamide to give(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide;

c) reacting (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formylformamide with an appropriate hydrolysis agent.

In addition, the present invention provides a novel process forcrystallizing alkali metal salts of diformylamide comprising the stepsof:

a) dissolving an alkali metal salt of diformylamide in a hydroxylicsolvent;

b) distilling the hydroxylic solvent while adding an anti-solvent.

In addition, the present invention provides for novel compounds of theformula: ##STR1## wherein X is chloro, bromo or--N(CHO)₂.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application:

a) the term "--N(CHO)₂ " refers to a radical of the formula; ##STR2## b)the term "halo" refers to a chlorine atom, a bromine atom, or an iodineatom;

c) the term "pharmaceutically acceptable salts" refers to acid additionsalts.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane.Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophosphate, and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includethe mono-, di-, and tricarboxylic acids. Illustrative of such acids arefor example, acetic, glycolic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, 2-phenoxybenzoic, and sulfonic acids such asp-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethanesulfonicacid. Such salts can exist in either a hydrated or substantiallyanhydrous form.

Examples of compounds encompassed by the present invention include:

(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane;

(E)-1-bromo-2-(fluoromethylene)-4-(p-fluorophenyl)butane;

(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide.

A general synthetic procedure is set forth in Scheme A. In Scheme A, allsubstituents unless otherwise indicated, are as previously defined.Reagents, techniques, and procedures used in Scheme A are well known andappreciated by one of ordinary skill in the art. ##STR3##

In Scheme A, step 1, 4-(p-fluorophenyl)butyric acid is contacted withisobutylene to give t-butyl 4-(p-fluorophenyl)butyrate.

For example, 4-(p-fluorophenyl)butyric acid is contacted withisobutylene. The reaction is carried out using 5% to 15% by weight of astrong acid catalyst, such as sulfuric acid, with 8% to 12% beingpreferred and 10% being most preferred. The reaction is tolerant of somewater in the starting material with the use of 4-(p-fluorophenyl)butyricacid containing less than 5% by weight water being preferred. Thereaction is carried out in isobutylene without a solvent. The reactionis carried out using 1 to about 5 molar equivalents of isobutylene, with2 to 4 molar equivalents being preferred and 3 molar equivalents beingmost preferred. The reaction can be carried out by combining4-(p-fluorophenyl)butyric acid and a strong acid catalyst and eitheradding the resulting mixture to isobutylene or preferably addingisobutylene to the resulting mixture. Regardless of the order ofaddition, cooling is required to control the exotherm that occurs duringmixing. When isobutylene is added to a 4-(p-fluorophenyl)butyricacid/sulfuric acid mixture, the mixture is cooled to a temperature ofbetween -30° C. and 0° C. before the addition of isobutylene, with -20°C. and -10° C. being preferred. The reaction is carried out at atemperature of from about 0° C. to about 40° C, with 10° C. to 30° C.being preferred and 20° C. to 25° C. being most preferred. The reactiongenerally requires from 3 to 12 hours. The product is obtained byquenching with a suitable base, such as sodium hydroxide or potassiumhydroxide, in the presence of isobutylene. The quench is carried out ata temperature of from about -5° C. to about 5° C. The product can beused after isolation by methods well known and appreciated in the art,such as extraction and evaporation. The product can be purified bymethods well known and appreciated in the art, such as distillation.

In Scheme A, step 2, t-butyl 4-(p-fluorophenyl)butyrate is contactedwith an appropriate alkyl chloroformate to give an alkyl2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate.

An appropriate alkyl chloroformate is one which transfers an alkoxycarbonyl group which allows for selective removal of the t-butyl ester,does not interfere with the difluoromethylation step or thedecarboxylative elimination step and can be subsequently reduced to givea hydroxymethyl group. Examples of an appropriate alkyl chloroformateinclude methyl chloroformate, ethyl chloroformate, propyl chloroformate,butyl chloroformate, isobutyl chloroformate, and the like, with ethylchloroformate being preferred.

For example, t-butyl 4-(p-fluorophenyl)butyrate is contacted with anappropriate alkyl chloroformate. The reaction is carried out in asuitable solvent such as tetrahydrofuran, or toluene/tetrahydrofuranmixtures. The reaction is carried out using from about 1 to about 2molar equivalents of a suitable base. A suitable base isnon-nucleophilic and is of sufficient strength to remove a proton fromthe methylene moiety adjacent to the carboxy group of the startingester. Suitable bases are known in the art, and include sodium hydride,sodium bis(trimethylsilyl)amide, lithium diisopropylamide, and the like.The reaction is carried out at a temperature of from about -78° C. toabout 0° C., with -20° C. 0° C. to being preferred. The formation ofby-products is minimized by the addition of t-butyl4-(p-fluorophenyl)butyrate to a solution of a suitable base followed byaddition of an appropriate alkyl chloroformate. The product can beisolated by methods well known and appreciated in the art, such asextraction and evaporation. The product can be purified by methods wellknown and appreciated in the art, such as chromatography anddistillation.

In Scheme A, step 3, an alkyl2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate is contacted with anappropriate difluoromethane transfer reagent to give an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate.

An appropriate difluoromethane transfer reagent is one that transfers adifluoromethyl group under the conditions of the reaction. Examples ofan appropriate difluoromethane transfer reagent includechlorodifluoromethane, bromodifluoromethane, and the like.

For example, an alkyl 2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate iscontacted with from 1.25 to 1.4 molar equivalents of an appropriatedifluoromethane transfer reagent. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, or toluene/tetrahydrofuranmixtures. The reaction is carried out using a suitable base. A suitablebase is non-nucleophilic and is of sufficient strength to remove aproton from the methine moiety adjacent to the carboxy groups of thestarting diester. Suitable bases having a sodium counter ion beingpreferred. Suitable bases are known in the art, and include sodiumhydride, sodium t-butoxide and sodium bis(trimethylsilyl)amide, withsodium bis(trimethylsilyl)amide being preferred and sodiumbis(trimethylsilyl)amide having a titration value of 2.1 or less beingmost preferred. The reaction is carried out at a temperature of fromabout 20° C. to about 50° C., with 40° C. to 45° C. being preferred. Thereaction generally requires 30 minutes to 2 hours. The product isobtained by quenching using a suitable acid, such as acetic acid. Thequench is carried out at a temperature of from about 15° C. to about 25°C. The product can be isolated by extraction and used as a solutionwithout purification or the product can be obtained as a solution inanother solvent by exchanging solvents by evaporation, as is well knownin the art. The product can be isolated and purified by methods wellknown and appreciated in the art, such as extraction, evaporation, anddistillation.

In Scheme A, step 2 and step 3 can be carried out without isolating thecompound of structure (3) formed in step 2, thus, a t-butyl4-(p-fluorophenyl)butyrate is contacted with an appropriate alkylchloroformate to give a reaction mixture and then the reaction mixtureis contacted with an appropriate difluoromethane transfer reagent togive an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate.

An appropriate alkyl chloroformate is as defined in Scheme A, step 2,and an appropriate difluoromethane transfer reagent is as defined inScheme A, step 3.

For example, t-butyl 4-(p-fluorophenyl)butyrate is contacted with anappropriate alkyl chloroformate. The reaction is carried out in asuitable solvent such as tetrahydrofuran, or toluene/tetrahydrofuranmixtures. The reaction is carried out using from about 2 to about 3molar equivalents of a suitable base. A suitable base isnon-nucleophilic and is of sufficient strength to remove a proton fromthe methylene moiety adjacent to the carboxy group of the startingester. Suitable bases having a sodium counter ion being preferred.Suitable bases are known in the art, and include sodium hydride, sodiumt-butoxide and sodium bis(trimethylsilyl)amide, with sodiumbis(trimethylsilyl)amide being preferred and sodiumbis(trimethylsilyl)amide having a titration value of 2.1 or less beingmost preferred. The reaction with an appropriate alkyl chloroformate iscarried out at a temperature of from about -70° C. to about 0° C., with-20° C. to 0° C. being preferred. The formation of by-products isminimized by the addition of t-butyl 4-(p-fluorophenyl)butyrate to asolution of a suitable base followed by addition of an appropriate alkylchloroformate.

After a time, generally, 10 minutes to 3 hours, a reaction mixture isobtained which comprises a substantial amount of an alkyl2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate, along with the selectedsuitable base, as a solution in the selected suitable solvent. Thereaction mixture is warmed to a temperature of from about 20° C. toabout 50° C., with 40° C. to 45° C. being preferred. The reactionmixture is then contacted with from 1.25 to 1.4 molar equivalents of anappropriate difluoromethane transfer reagent. Generally, the reactionwith an appropriate difluoromethane transfer reagent requires 30 minutesto 2 hours. The product is obtained by quenching using a suitable acid,such as acetic acid. The quench is carried out at a temperature of fromabout 15° C. to about 25° C. The product can be isolated by extractionand used as a solution without purification or the product can beobtained as a solution in another solvent by exchanging solvents byevaporation, as is well known in the art. The product can be isolatedand purified by methods well known and appreciated in the art, such asextraction, evaporation, and distillation.

In Scheme A, step 4, an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate withan appropriate acid to give an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate.

For example, an alkyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate iscontacted with 5% to 30% by weight of an appropriate acid. Anappropriate acid is an organic or inorganic acid which serves as acatalyst for the removal of a t-butyl ester but does not cause theformation of detrimental by-products. Examples of an appropriate acidinclude trifluoroacetic acid, methanesulfonic acid, sulfuric acid,hydrochloric acid, formic acid and the like, with methanesulfonic acidand trifluoroacetic acid being preferred and methanesulfonic acid beingmost preferred. The reaction is carried out either without a solvent orwith a suitable solvent, such as toluene, tetrahydrofuran, ortoluene/tetrahydrofuran mixtures. The use of a solvent is preferred.When a solvent is used, toluene is preferred. The reaction is carriedout at a temperature of from about 20° C. to about 60° C., with 40° C.to 50° C. being preferred. The product can be isolated by extraction togive the product as a solution. The product can be purified bytechniques well known in the art, such as evaporation, andrecrystallization. The product can also be extracted into water using anappropriate base and used as an aqueous solution of its salt in the nextstep without purification.

In Scheme A, step 5, an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate is contactedwith an appropriate base to give an alkyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate.

An appropriate base is any base capable of removing the carboxy protonof an alkyl 2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate in adecarboxylative elimination reaction to give(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate. Appropriate basesinclude triethylamine, sodium bicarbonate, sodium carbonate, sodiumhydroxide, potassium hydroxide, and the like.

For example, an alkyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate is contactedwith an essentially equimolar amount of an appropriate base. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,toluene, water or tetrahydrofuran/water mixtures withtetrahydrofuran/water mixtures being preferred and tetrahydrofuran/watermixtures of around 1 to 1 by weight being most preferred. The reactionis carried out at a temperature of from about -10° C. to about 40° C.,with 0° C. to 25° C. being preferred. The reaction generally requiresfrom 1 to 6 hours. The product can be isolated by techniques well knownin the art, such as extraction and evaporation. The product can also bepurified by techniques well known in the art, such as chromatography anddistillation.

In Scheme A, step 6, an alkyl(E)-2-(fluoromethylene)4-(p-fluorophenyl)butyrate is contacted with anappropriate reducing agent to give(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol.

An appropriate reducing agent is one that is capable of reducing theester group of an alkyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate in the presence ofthe fluoromethylene group. Appropriate reducing agents include sodiumborohydride, lithium borohydride, potassium tri-sec-butylborohydride,9-borabicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminumhydride, and the like, with diisobutylaluminum hydride being preferred.

For example, an alkyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrateis contacted with about 2.0 to about 3.0 equivalents of an appropriatereducing agent. The reaction is carried out in a suitable solvent, suchas hexane, cyclohexane, dichloromethane, tetrahydrofuran, or toluene,with tetrahydrofuran and toluene being preferred and toluene being mostpreferred. The reaction is carried out by either adding a solution of analkyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate to a solutionof an appropriate reducing agent or adding a solution of an appropriatereducing agent to a solution of an alkyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate. The addition iscarried out at a temperature of from about -30° C. to about 10° C. Thereaction is carried out at a temperature of from about 0° C. to about30° C. The reaction generally requires 2 to 5 hours. The product can beisolated by quenching and extraction. The quench is carried out at atemperature of from about -15° C. to about 0° C. The product can beisolated as a solution by methods well known and appreciated in the art,such as extraction and evaporation. The product can be purified as iswell known in the art by chromatography and distillation.

In Scheme A, step 7,(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol is contacted withan appropriate halogenating agent to give a(E)-1-halo-2-(fluoromethylene)-4-(p-fluorophenyl)butane.

An appropriate halogenating agent is one that converts a hydroxyl groupto a halo group and does not cause the degradation of the the startingmaterial or the product. Appropriate halogenating reagents are wellknown in the art and include, phosphorous trichloride, phosphoroustribromide, thionyl chloride, thionyl bromide, oxalyl chloride, theVilsmeier reagent, and the like. As is well known in the art, theVilsmeier reagent can be formed utilizing either a catalytic amount orslight molar excess of N,N-dimethylformamide and various chlorinatingagents, such as phosphoryl chloride, phosgene, phosphorous trichloride,and oxalyl chloride.

For example, (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol iscontacted with 1.0 to 1.5 molar equivalents of an appropriatehalogenating agent. The reaction is carried out in a suitable solvent,such as dichloromethane and toluene. The reaction is carried out at atemperature of from about 20° C. to about 30° C. The reaction generallyrequires 4 to 24 hours. The product can be isolated by quenching withaqueous sodium chloride solution, extraction, and evaporation. Theproduct can be purified as is well known in the art by chromatographyand distillation.

In Scheme A, step 8, a(E)-1-halo-2-(fluoromethylene)4-(p-fluorophenyl)butane is contacted withan alkali metal salt of diformylamide to give(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide.

Examples of an alkali metal salt of diformylamide, include sodiumdiformylamide, potassium diformylamide, and the like.

For example, a (E)-1-halo-2-(fluoromethylene)-4-(p-fluorophenyl)butaneis contacted with 1.0 to 1.6 molar equivalents of an alkali metal saltof diformylamide. The reaction may be carried out in the presence of0.05 to 0.5 molar equivalents of a suitable catalyst, such as sodiumiodide or potassium iodide. The reaction is carried out in a suitablesolvent, such as N-methylpyrrolidinone, N,N-dimethylformamide,acetonitrile, N-methylpyrrolidinone/acetonitrile mixtures,N,N-dimethylformamide/acetonitrile mixtures, orN,N-dimethylformamide/acetonitrile/toluene mixtures. The reaction iscarried out at a temperature of from about 50° C. to about 90° C. Thereaction generally requires 2 to 24 hours. The product can be isolatedby quenching and extraction. The product can be purified as is wellknown in the art by chromatography and recrystallization.

In Scheme A, step 9,(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamideis contacted with an appropriate hydrolysis agent to give(E)-1-amino-(2-fluoromethylene)-4-(p-fluorophenyl)butane.

Appropriate hydrolysis agents are well known in the art including alkalimetal hydroxides, such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like, and aqueous solutions of acids, such ashydrochloric acid, hydrobromic acid, and the like. For example,(E)-N-(2-(fluoromethylene)-4-(P-fluorophenyl)butyl)-N-formyl formamideis contacted with an appropriate hydrolysis agent. The reaction iscarried out in a suitable solvent, such as water, methanol, ethanol,methanol/water mixtures, ethanol/water mixtures, andtetrahydrofuran/water mixtures. The reaction is carried out at atemperature of from about 0° C. to about 150° C. The reaction generallyrequires 2 to 24 hours. The product can be isolated by quenching andextraction. The product can be purified as is well known in the art bychromatography and recrystallization.

In Scheme A, optional step 10,(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane is contacted,as is well known in the art, with an appropriate pharmaceuticallyacceptable acid to form a pharmaceutically acceptable acid additionsalt.

Alkali metal salts of diformylamide, such as lithium diformylamide,sodium diformylamide, and potassium diformylamide are obtained as agranular solid by a novel crystallization process comprising the stepsof: dissolving an alkali metal salt of diformylamide in a hydroxylicsolvent and removing the hydroxylic solvent by distillation while addingan anti-solvent.

For example, an alkali metal salt of diformylamide is dissolved in ahydroxylic solvent, such as methanol, ethanol, propanol, isopropanol,butanol, and the like, with methanol being preferred. The volume ofhydroxylic solvent used is not critical but should be kept to a minimalamount as a matter of convenience. The solution is heated to thetemperature at which the hydroxylic solvent begins to distill and ananti-solvent is added to replace the hydroxylic solvent lost upondistillation. Examples of an anti-solvent include benzene,chlorobenzene, toluene, xylene, cyclohexane, hexane, cyclopentane,heptane, octane, isooctane, dichloromethane, acetonitrile, ethylacetate, acetone, butanone, and tetrachloroethylene, with benzene,toluene, cyclohexane, and acetonitrile being preferred and toluene beingmost preferred. Distillation is continued until the alkali metal salt ofdiformylamide crystallizes. The volume of the solution being decreasedas necessary to facilitate crystallization. The distillation may becontinue until the hydroxylic solvent is substantially removed. Thealkali metal salt of diformylamide is isolated by filtration and dried.

The foregoing processes are exemplified by the procedures given below.These procedures are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in theprocedures, the following terms have the meanings indicated: "g" refersto grams; "kg" refers to kilograms; "mol" refers to moles; "mmol" refersto millimoles; "mL" refers to milliliters; "L" refers to liters; "bp"refers to boiling point; "mp" refers to melting point; "lb" refers topounds; "° C." refers to degrees Celsius; "dec" refers to decomposition;"M" refers to molar; "psi" refers to pounds per square inch.

Preparation of (E)-2-(fluoromethylene)-4-p-fluorophenyl)butan-1-ol

1.1 Synthesis of t-butyl 4-(p-fluorophenyl)butyrate

Scheme A, step 1: ##STR4##

Combine 4-(p-fluorophenyl)butyric acid (51.4 g) and sulfuric acid (5.28g, 98% Reagent ACS) in a Fisher-Porter bottle. Cool with a dry-ice bathto an internal temperature of between 0° C. and -20° C. Add isobutylene(54 g). Warm to ambient temperature. After 3 hours, cool in adry-ice/acetone bath until the internal pressure differential of thevessel was 0 psi or less (about -20° C.). Carefully vent theFisher-Porter bottle and add a cold solution of 5 M sodium hydroxide(51.5 g). Reseal the Fisher-Porter bottle and allow to warm to ambienttemperature with vigorous stirring. Vent the Fisher-Porter vessel toremove excess isobutylene. Extract the reaction mixture with toluene (75g). Separate the organic layer and extract with a saturated sodiumbicarbonate solution (77 g). Evaporate in vacuo to obtain the titlecompound. ¹ H NMR (CDCl₃, 300 MHz) δ1.45 (s, 9H), 1.84 (m, 2H) 2.23 (t,J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 6.96 (m, 2H), 7.13 (m, 2H).

2.1 Synthesis of ethyl 2-(t-butoxycarbonyl)-4-(P-fluorophenyl)butyrate

Scheme A, step 2: ##STR5##

Prepare a solution of lithium diisopropylamide from diisopropylamine(22.74 g) and 1.6M n-butyl lithium (143.7 mL) in tetrahydrofuran (200mL). Cool to -78° C. Slowly add t-butyl 4-p-(fluorophenyl)butyrate(26.76 g) as a solution in tetrahydrofuran (100 mL). After 1 hour, addethyl chloroformate (12.19 g) as a solution in tetrahydrofuran (100 mL).After 24 hours, pour the reaction mixture into water, neutralize withdilute aqueous hydrochloric acid solution. Extract with diethyl ether.Dry the organic layer over MgSO₄, filter, and evaporate in vacuo to givethe title compound.

3.1 Synthesis of ethyl2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate

Scheme A, step 3: ##STR6##

Combine ethyl 2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate (32.14 g)and sodium t-butoxide (19.81 g) in tetrahydrofuran (400 mL). Stir themixture for 1 hour, then heat to 45° C. Add an excess ofchlorodifluoromethane over about 15 minutes. After 1 hour under anatmosphere of chlorodifluoromethane, allow the temperature to fall toambient. Pour the reaction mixture into water/brine. Extract withdiethyl ether. Dry the organic layer over MgSO₄, filter, and evaporatein vacuo to give the title compound.

3.2 Synthesis of ethyl2-(difluoromethyl),2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate

Scheme A, step 2 and Scheme A, step 3:

Cool a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (545kg, 2M, 877 mol) to -10° C. Slowly add, t-butyl4-(p-fluorophenyl)butyrate (84.1 kg, 80% by weight in toluene, 353 mol).After 15 minutes, slowly add ethyl chloroformate (38.6 kg, 356 mol) atsuch a rate that the reaction temperature is maintained at or below -5°C. After 20 minutes, warm the reaction mixture to 40° C.-45° C. Seal thereaction vessel and add chlorodifluoromethane (38.15 kg, 445 mol) to thehead space. After 1 hour, cool to 15° C. -20° C. and vent the reactionvessel. Add a solution of acetic acid (421 kg, 20% in water) and stir.After 30 minutes, separate the aqueous layer and evaporate the organiclayer in vacuo to obtain a residue. Add toluene (45 kg) and evaporate invacuo until the internal temperature of the reaction vessel is 55° C. toobtain the title compound as a toluene solution.

4.1 Synthesis of ethyl2-(difluoromethyl)-2-carboxy-4-(P-fluorophenyl)butyrate

Scheme A, step 4: ##STR7##

Add methanesulfonic acid (47.7 kg, 496 mol) to a toluene solution ofethyl 2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrateas prepared in Example 3.1 at a temperature of 40° C. 50° C. After 3 to6 hours, cool the reaction to ambient temperature. Add toluene (91 kg)and water (421 kg) and stir for 30 minutes. Separate the aqueous layer.Add to the organic layer a 20% by weight solution of sodium chloride inwater (420 kg) and stir for 30 minutes. Separate the layers to give thetitle compound as a solution in toluene.

5.1 Synthesis of ethyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate

Scheme A, step 5: ##STR8##

Cool to 0° C.-10° C. a toluene solution of ethyl2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate as prepared inExample 4.1. Add water (396 kg) and a 50% by weight aqueous solution ofsodium hydroxide. Stir for 30 minutes. Separate the aqueous layer andcool the aqueous layer to 0° C.-5° C. Add tetrahydrofuran (421 kg). Stirfor 1 hour at 0° C. and then warm to 25° C. and stir for 3 hours.Separate the aqueous layer. Evaporate the organic layer in vacuo at atemperature of 40° C.-50° C. The evaporation is continued untiltetrahydrofuran no longer comes over and then toluene is added.Evaporate in vacuo until there is no longer water visible in thecondensate. Concentrate in vacuo to give the title compound as a 80-90%by weight solution in toluene. An analytical sample prepared byevaporation of solvent gave ₁ H NMR (CDCl₃, 300 MHz) δ1.28 (t, J=7.2 Hz3H), 2.58 (m, 2H), 2.71 (m, 2H) 4.21 (q, J=7.2 Hz, 2H), 6.93 (m, 2H),7.15 (m, 2H), 7.51 (d, J=81.9 Hz, 1H).

6.1 Synthesis of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol

Scheme A, step 6: ##STR9##

Combine ethyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.5 g,6.24 mmol) and toluene (5 mL). Cool to -15° C. Add dropwise, a solutionof diisobutylaluminum hydride (10.4 mL, 1.5M in toluene, 15.6 mmol).Warm to ambient temperature. After 18 hours, cool to 0° C. With vigorousstirring add sequentially, methanol (15 mL), an aqueous 5M hydrochloricacid solution (25 mL), and water (35 mL). When gas evolution ceases,extract with toluene. Separate the layers and evaporate organic layer invacuo to give the title compound. ¹ H NMR (CDCl₃, 300 MHz) δ2.28 (s,1H), 2.45 (m, 2H), 2.72 (m, 2H) 3.91 (d, J=3 Hz, 2H), 6.57 (d, J=87 Hz,1H), 6.96 (m, 2H), 7.13 (m, 2H).

6.2 Synthesis of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol

Scheme A, step 6:

Cool to 0° C. a solution of diisobutylaluminum hydride (7.64 kg, 25% byweight in toluene, 13.42 mol). Add a solution of ethyl(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.74 kg, 74.1% byweight in toluene, 5.37 mol) at such a rate that the temperature of thereaction mixture does not rise above 20° C. After the addition iscomplete, warm to ambient temperature. After 2 hours, cool to 0° C.Slowly, add methanol (7.73 kg) at such a rate that the temperature ofthe reaction mixture does not rise above 15° C. Cool to 0° C. Slowly,add water (7.96 kg) at such a rate that the temperature of the reactionmixture does not rise above 20° C. Add a concentrated aqueous solutionof hydrochloric acid (7.59 kg). Warm to ambient temperature. Separatethe organic layer and dry azeotropically by distillation in vacuo untilthe volume of the organic layer is about one half of its original volumeto give the title compound as a solution in toluene.

Preparation of (E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane

7.1 Synthesis of(E)-1-bromo-2-(fluoromethylene)-4-(p-fluorophenyl)butane

Scheme A, step 7: ##STR10##

Combine (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan1-ol (4.0 g, 20.2mmol) and toluene (10 mL). Cool to about -5° C. Add dropwise, a solutionof phosphorous tribromide (1.8 g, 6.65 mmol) in toluene (5 mL). After 1hour, warm to ambient temperature. After 18 hours, cool to 0° C. andthen add saturated sodium bicarbonate solution (50 mL). Separate thelayers and extract the aqueous layer 3 times with toluene (40 mL).Extract the combined organic layers with a saturated aqueous sodiumchloride solution, dry over Na₂ SO₄, filter, and evaporate in vacuo togive the title compound.

7.2.1 Synthesis of(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane

Scheme A, step 7: ##STR11##

Combine oxalyl chloride (2.71 g, 21.4 mmol) and toluene (20 mL). Cool to0° C. Add N,N-dimethylformamide (1.62 g, 22.2 mmol) as a solution intoluene (2 mL). Warm to ambient temperature. After 10 minutes, cool to0° C. Add (E)-2(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (4.0 g,20.2 mmol) Warm to ambient temperature. After 18 hours, pour thereaction mixture into a saturated sodium chloride solution (100 mL).Extract the aqueous layer 3 times with toluene. Dry the combined organiclayers over Na₂ SO₄, filter, and evaporate in vacuo to give the titlecompound. ¹ H NMR (CDCl₃, 300 MHz) δ2.52 (m, 2H), 2.75 (m, 2H), 3.91 (d,J=6 Hz, 2H), 6.65 (d, J=82.5 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 2H).

7.2.2 Synthesis of(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane

Scheme A, step 7:

Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Coolto -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution intoluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (24.7 g, 30% byweight in toluene, 0.124 mol). After 18 hours, add water (500 mL) andstir for 30 minutes. Separate the organic layer, dry over Na₂ SO₄,filter, and evaporate in vacuo to give the title compound.

8.1.1 Synthesis of(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide

Scheme A, step 8: ##STR12##

Combine sodium diformylamide (28.8 g, 0.31 mol), acetonitrile (360 g),and N,N-dimethylformamide (48 g). Add(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (50.6 g, 0.23mol). Heat to reflux. After 5 hours, cool to ambient temperature. Addwater (466 g) and stir for 15 minutes. After 30 minutes, the aqueouslayer is removed. Evaporate the organic layer in vacuo to give the titlecompound. ¹ H NMR (CDCl₃, 300 MHz) δ2.28 (m, 2H), 2.72 (m, 2H), 4.07 (d, J=3Hz, 2H), 6.74 (d, J=81Hz, 1H), 6.94 (m, 2H), 7.13 (m, 2H), 8.73 (s,2H).

8.1.2 Synthesis of(E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide

Scheme A, step 8:

Combine sodium diformylamide (70 lb) and acetonitrile (903 lb). Withagitation, add N,N-dimethylformamide (119 lb). Add a solution of(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (126 lb) intoluene. Warm to 80° C. After 6 hours, add a 10% by weight solution ofsodium chloride in water (1168 lb). Agitate for 15 minutes, separate thelayers. Remove the organic layer to give the title compound as asolution in acetonitrile/N,N-dimethylformamide.

9.1.1 Synthesis of(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane hydrochloridesalt

Scheme A, step 9 and Scheme A, optional step 10: ##STR13##

Combine (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formylformamide (8.0 g, 32.7 mmol), ethanol (19.9 g), water (29.8 g), andaqueous 12M hydrochloric acid solution (13.1 g). Heat to reflux. After 1hour, add toluene (29.8 g). Cool to 25° C. Separate the layers. Distillthe aqueous layer until the volume is reduced by about two thirds. Coolto 50° C. Add concentrated aqueous hydrochloric acid solution (50 g).Cool to -5° C., filter , rinse with toluene, and dry in vacuo at 60° C.to give a solid. Recrystallize the solid from isopropyl acetate, filter,and dry in vacuo at 43° C. to give the title compound: mp 130°-131.5° C.1H NMR (D20, 300 MHz) 8 2.50 (m, 2H), 2.79 (m, 2H), 3.47 (d, J=3.0 Hz,2H), 6.80 (d, J=81.9 Hz, 1H), 7.09 (m, 2H), 7.28 (m, 2H).

9.1.2 Synthesis of(E)-1-amino-2-(fluoromethylene)-4-(p-fluorophenyl)butane hydrochloridesalt

Scheme A, step 9 and Scheme A, optional step 10:

Evaporate a acetonitrile/N,N-dimethylformamide solution of crude (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl) -N-formyl formamide asprepared in Example 8.1. 2 (1951.5 lb, 12.9% by weight of(E)-N-(2(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide)Combine (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl) butyl)-N-formylformamide (252 lb) obtained by evaporation above, ethanol (504 lb),water (760), and aqueous 12M hydrochloric acid solution (328 lb). Heatto 81° C.-89° C. After 2.5 hour, add toluene (784 lb) stir and separatethe layers. Evaporate the aqueous layer in vacuo until about 80-110gallons of liquid remain. Add concentrated aqueous hydrochloric acidsolution (1678 lb). Cool to 0° C. over 6 hours, to give a solid. Collectthe solid by filtration, rinse with toluene, and dry in vacuo at 60° C.to give the title compound.

Process for crystallizing alkali metal salts of diformylamide

10.1 Synthesis and Crystallization of sodium diformylamide

Combine a solution of sodium methoxide (801.6 g, 25% by weight inmethanol, 3.71 mol) and formamide (334 g, 7.42 mol). After 1 hour, heatto reflux. Remove methanolic ammonia by distillation. Continue thedistillation, add toluene (800 g) dropwise at a rate approximately equalto the rate of solvent loss. Distill until the temperature of the stillhead reaches 110° C. Cool to ambient temperature, filter and dry to givesodium diformylamide as a granular solid: mp 185-190 (dec).

10.2 Crystallization of sodium diformylamide

Combine sodium diformylamide (352.5 g, 3.71 mol) and methanol (290 g) ina suitable distillation apparatus. Heat until methanol begins todistill. As the distillation proceeds, add toluene (800 g) dropwise at arate approximately equal to the rate of solvent loss. Distill until thetemperature of the still head reaches 110° C. Cool to ambienttemperature, filter and dry to give sodium diformylamide.

10.3 Crystallization of potassium diformylamide

Combine potassium diformylamide (392 g, 3.5 mol) and ethanol (400 g) ina suitable distillation apparatus. Heat until ethanol begins to distill.As the distillation proceeds, add toluene (1000 g) dropwise at a rateapproximately equal to the rate of solvent loss. Distill until thetemperature of the still head reaches 110° C. Cool to ambienttemperature, filter and dry to give potassium diformylamide.

What is claimed is:
 1. The compound(E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane.
 2. Thecompound (E)-1-bromo-2-(fluoromethylene)-4-(p-fluorophenyl)butane.